Induction of periosteal bone formation by intraosseous BMP-2 injection in a mouse model of osteogenesis imperfecta

Abstract

PurposeSurgical interventions are routinely performed on children with osteogenesis imperfecta (OI) to stabilize long bones, often post fracture. We speculated that a combination of intramedullary reaming and intraosseous injection of recombinant bone morphogenetic protein-2 (BMP-2) could enhance periosteal ossification and ultimately cortical thickness and strength. This approach was conceptually tested in a preclinical model of genetic bone fragility.MethodsSix experimental groups were tested including no treatment, intramedullary reaming, and reaming with 5 µg BMP-2 injection performed in the tibiae of both wild type (WT) and Col1a2G610C/+ (OI, Amish mutation) mice. Bone formation was examined at a two-week time point in ex vivo specimens by micro-computed tomography (microCT) analysis and histomorphometry with a dynamic bone label.ResultsMicroCT data illustrated increases in tibial cortical thickness with intramedullary reaming alone (Saline) and reaming plus BMP-2 injection (BMP-2) compared to no intervention controls. In the OI mice, the periosteal bone increase was not statistically significant with Saline but there was an increase of +192% (p = 0.053) with BMP-2 injection. Dynamic histomorphometry on calcein label was used to quantify new woven bone formation; while BMP-2 induced greater bone formation than Saline, the anabolic response was blunted overall in the OI groups.ConclusionsThese data indicate that targeting the intramedullary compartment via reaming and intraosseous BMP-2 delivery can lead to gains in cortical bone parameters. It is suggested that the next step is to validate safety and functional improvements in a clinical OI setting.

Osteogenic and Chondrogenic Potential of Periosteum-Derived Mesenchymal Stromal Cells: Do They Hold the Key to the Future?

“…Intraosseous 5 µg BMP-2 injection in a mouse model of osteogenesis imperfecta resulted in periosteal ossification and enhanced biomechanical strength and thickness of cortical bone [69]. Endosteal and periosteal osteogenesis was ascertained in chronic ovariectomized female cynomolgus monkeys with an intraosseous injection of recombinant BMP-2 loaded into calcium phosphate matrix into the femoral neck [70].…”

The recombinant BMP-2 loaded silk fibroin microspheres improved the bone phenotype of mild osteogenesis imperfecta mice

“…Following the treatment of teriparatide, sclerostin antibody, and transforming growth factor- β (TGF- β ) antibody, osteoblastic bone production has been observed to be enhanced in several kinds of OI ( Nicol et al, 2021 ; Sinder et al, 2014 ; Tauer, Abdullah & Rauch, 2019 ). The utilization of multiple osteogenic inducing agents, including bone morphogenetic protein-2 (BMP-2) and Nell1, has been observed to yield favorable results in the treatment of OI ( Cheng et al, 2019 ; Liu et al, 2020 ). However, the relatively rapid clearance and diffusion rates of these exogenous drugs or factors frequently necessitate high dosages and multiple administrations.…”

Modeling anabolic and antiresorptive therapies for fracture healing in a mouse model of osteogenesis imperfecta

“…Large randomized clinical trials have supported the use of rhBMP‐2 for treating nonunion and spine fusion, 7,8 but comparable studies are lacking in the context of OI. Our team previously published a model for intramedullary delivery of BMP‐2 to increase cortical thickness in a mouse model of OI 9 . The model featured biological induction of bone growth with BMP‐2 combined with mechanical disruption by reaming.…”

“…Our team previously published a model for intramedullary delivery of BMP-2 to increase cortical thickness in a mouse model of OI. 9 The model featured biological induction of bone growth with BMP-2 combined with mechanical disruption by reaming. Forced BMP-2 expression has also been historically suggested as a gene/cell therapy approach for OI.…”